Abstract

At present antiretroviral treatment has become a standard practice in treating HIVinfected individuals worldwide. With the need for a lifelong treatment, long term side effect of antiretroviral agents is an emergent issue of concern. We describe a perinatally HIV-infected adolescent female patient who developed gigantomastia while receiving efavirenz-based antiretroviral regimen. The diagnosis was confirmed by ultrasonography and mammography. The increase breast size interfered with her quality of life. Moreover, it did not improve after treatment modification (replacement of efavirenz with nevirapine) following by hormonal therapy (anti-estrogen). Breast reduction was performed. Although it is rare, physicians should be aware of this condition so that a timely diagnosis can be made. In most cases, only conservative treatment is sufficient, but in severe cases surgical intervention might be required.

Keywords

Therapy, Children, HIV

Background

Highly Active Antiretroviral Therapy (ART) has been
available in Thailand since the year 1997; the natural
history of people infected with HIV virus was changed
since then [1]. Under Thai national program supported
by Thai government since 2002, HIV-infected adults and
children could survive longer; perinatally HIV-infected
children could grow-up entering adolescent years and
adulthood. However, when many have been placed on
treatment, increasing number of individuals with adverse
effects from long term use of ART was reported. Metabolic
disorders including dyslipidemia, lipodystrophy, and
impaired glucose tolerance were observed [2]. Breast
hypertrophy or abnormal breast enlargement could be due
to accumulation of fat tissue known as macromastia or
lipomastia, and may be a part of lipodystrophy syndrome
seen in HIV-infected patients on ART [3]. Another condition
is a change in physical characteristic, breast enlargement
in HIV-infected individuals treated with ART has been
reported from several countries [4-8]. Gynecomastia,
proliferation of glandular breast tissue, is the term used
to describe abnormal breast enlargement usually in males.
Similar condition in female is called breast hypertrophy,
or gigantomastia in case of extreme breast enlargement.
The patient can present with neck, shoulder, or back pain,
skin irritation or intertrigo resulting from breast size [9].
Emotional disturbance and effects on health-related quality
of life were also reported [10]. The differential diagnoses
include effect of external hormones or other concomitant
drugs used, estrogen-androgen imbalance in adolescents
and benign or malignant breast diseases.

Case Presentation

A 15 year and 2 month old girl with perinatally HIVinfection
presented with bilateral breast enlargement. She
was diagnosed as having HIV infection in early childhood
when blood test during health check-up was performed.
Without history of opportunistic infections or any HIVrelated
diseases, she has been initiated on ART at the age of
8 years. The girl was also diagnosed as having intellectual
disability and attention deficit hyperactivity disorder. She
has attended special educational school for several years.
Later she quitted school as her grandmother decided that
she should better be reared up at home. Her recent ART
regimen which composed of lamivudine, zidovudine and
efavirenz has been taken for 4 years. Other concomitant
medications included risperidone and clonazepam.

When the girl was 15 years old, her mother noticed her
exaggerated breast growth. She observed it for a few
months before reporting to the HIV pediatrician. No pain
or tenderness was noted. Physical examination revealed
that the breasts were generalized increase in size without
palpable mass. There were no other signs of lipodystrophy.
Ultrasonography and mammogram demonstrated no
evidence of solid mass or cystic lesion. A clinical diagnosis
of medication-induced gynecomastia was considered.
The pediatrician modified her ART regimen by replacing
efavirenz with rilpivirine. Three months later when the girl
came back for her scheduled follow-up visit, the breast size
did not decrease. Moreover the girl felt much worried and
anxious about her breast appearance. She talked less and
denied food intake due to the fear that it might make her
breast size become even larger. Adult HIV specialist and
psychologist have been consulted, and her ART regimen
was then modified to tenofovir, lamivudine and rilpivirine.

A month after the revision of her ART regimen and
withdrawal of EFV, there was no regression in the size
of her breast leading to persistence of her depression. She
began to keep isolation in the house and denied any social
interaction. Her mother requested for surgery. Thus, she
was transferred to the tertiary care hospital for evaluation
and management plan.

Hormonal treatment was prescribed; tamoxifen 20 mg/
day was given orally. On the 3 month follow-up visit, the
breast consistency was softer but did not decrease in size.
After 6 months on hormonal therapy, surgical reduction
was advised by endocrinologist and plastic surgeon that
have been consulted and followed her condition. However,
after the first counselling session with her caregivers, an
agreement about surgical procedure could not be reached.
They had fear of wound care after surgery and were afraid
of other potential post-operative complications. The
surgeon advised withholding the operation until they were
ready. Thus, the girl remained on tamoxifen for other few
months. Finally the caregivers came up and gave their
consent for the surgery. Reduction mammoplasty with
free nipple graft was eventually conducted. There were
two specimens obtained, one was from right mastectomy,
measuring 25.5 × 19 × 5 cm with 23 × 6 cm skin and 20 × 14 × 3 cm separated soft adipose tissue. Another specimen
was from left mastectomy, measuring 26 × 17 × 5.5 cm
with 21 × 14 cm skin and 16 × 8 × 2 cm separated soft
adipose tissue. Pathological results reported benign breast
tissue with the presence of benign duct, rarely acini and
increase fibrous stroma. No malignancy seen. There
were no post-operative complications. When she came
to a follow-up visit a month after hospital discharge, she
recovered with good wound healing. Only minimal scar
was observed (Figure 3).

Figure 3: Minimal scar was observed

Discussion

We report a case of gynecomastia in a perinatally HIVinfected
adolescent girl while receiving efavirenz-based
ART. Efavirenz, as well as protease inhibitors was
consistently reported as associated with this anatomical
change; it is suspected to have direct estradiol-like effects
which can trigger the growth of breast tissue by binding to estrogen-receptor-alpha in the breast resulting in breast
hypertrophy or gynecomastia, as well as modulation
of estrogen receptor [11-13]. Moreover, similar to
protease-inhibitors, effect of efavirenz on cytochrome
P-450 inhibition might lead to an increase in estradiol
concentration [14]. In this patient, we found high LH
and estradiol levels, but normal FSH. Treatment with
pharmacotherapeutic approach to control breast size has
been attempted; Tamoxifen which was an anti-estrogen
was prescribed. However, it did not seem to be effective.
Apart from antiretroviral agents, other possible causes of
gynecomastia include other medications, tumors, certain
genetic syndromes, obesity, hyperthyroidism, chronic
renal and liver diseases [4]. They are needed to be ruled
out by history taking, clinical finding, or investigations. In
this patient no evidence of such conditions found.

Regarding the effect of ART on breast, there were many
case reports among HIV-infected adults from previous
literature reviews. A case series of 6 patients from France
in 2001 reported an increase in breast size among 4 men
and 2 women aged 43-55 years being treated with efavirenz
as a part of ART for HIV infection. The breast enlargement
was not progressive and abated overtime even if the drug
was continued without change [5]. The Spanish report
included 5 HIV-infected male and female adults aged
range from 30-47 years who received efavirenz for the
duration of 4-15 months had gynecomastia. Efavirenz was
withdrawn after diagnosis confirmed with ultrasonography,
mammography and hormonal tests; regression in breast
size was observed in the mean duration of 5 months after
replacement [6].

The prevalence of breast hypertrophy in children and
adolescents was supposed to be lower than adults
as pediatric reports were rather scarce. According to
the report from Ugandan pediatric ART study, breast
hypertrophy was seen in one of 162 children initiated
on efavirenz-based regimen at 52 weeks after treatment
initiation [7]. A case report from South Africa was a 7
year old girl who has been on efavirenz for 10-12 weeks
when presented with breast hypertrophy without other
signs of puberty. Blood test confirmed all hormone levels
were within normal range, switching from efavirenz
to nevirapine was made. The breast enlargement was
completely resolved in 4 weeks [8]. Another report from
the UK was a 15 year old HIV-infected Kenyan boy
treated with efavirenz-including regimen for 2 years.
Bilateral breast enlargement was observed, and treatment
with percutaneous hormonal cream was tried following by
ART regimen modification. The conservative treatment
attempts did not result in improvement and the boy had
depressive symptoms (homebound and separated from his
peers); he finally underwent bilateral mastectomy and true
gynecomastia was confirmed by pathologic report which
revealed proliferation of breast ducts without lobular unit
[10]. The latter was quite similar to ours, except that our
patient was a female. Breast hypertrophy was needed to
be distinguished from pseudogynecomastia or lipomastia
which was a characteristic of lipodystrophy syndrome
and might be accompanying with other lipodystrophic features. Ultrasonography and mammography are useful
either to confirm diagnosis and to rule out mass or cystic
lesions. They are non-invasive and can be performed in
most clinical care settings. Next, blood hormone levels
might help in determining whether there is an increase in
estrogen or other related hormone levels. In our patient,
despite of increase in serum estradiol level, treatment
with anti-estrogen was not found to be effective. Part of
it might be due to the fact that the diagnosis and treatment
was delayed as the girl had pre-existing mental problem
which inhibited her from telling her caregivers about the
change in breast size. When recognized, it was much
larger beyond the reversible point. Early developed
gynecomastia can resolve when the causes were removed,
i.e., drug withdrawn. However, it might not possible in
a long term gynecomastia with the presence of fibrotic
tissue [11,12]. However, the change in breast consistency
confirmed effect of estrogen. In severe case like our
patient, the abnormal breast size brought her discomfort,
difficulty in daily living and some signs of depression.
Surgical management was considered in order to retain
optimal quality of life which was crucial especially for
HIV-infected adolescents. In this case there was low
risk of recurrence since the most likely drug related to
gigantomastia has been discontinued.

Currently efavirenz is a part of the first-line ART for
most HIV-infected populations recommended by the
World Health Organization (WHO); it is significant that
physicians should be aware of this unusual side effect so
that it can be recognized in a timely manner. Change in
breast size can cause both physical limitations due to the weight of the breasts, as well as psychological/psychiatric
problems. Treatment options include ART regimen
modification, hormonal therapy or surgery depending on
the discussion between physician and patient/caregivers
on a case-by-case basis. Nevertheless, surgical treatment
should only be reserved for cases of massive breast
hypertrophy where quality of life is obviously affected.

Conclusion

Gigantomastia is one among adverse events from long
term antiretroviral treatment, specifically efavirenzbased
regimen. Change in breast size can affect both
physical and mental health of adolescent. Although it
is rare, appropriate and timely diagnosis can be made
if physicians and/or health care providers are aware of
this condition. Available treatment options include ART
regimen modification, hormonal therapy and surgery
which should only be reserved for severe cases.

Acknowledgement

The authors would like to thank the patient and her family.
We gratefully acknowledge all medical consultants and
health care providers in Chiang Mai university hospital
and Chiangrai Prachanukroh Hospital for taking care of
this patient. We also thank Rawiwan Hansudewechakul
MD, at Chiangrai Prachanukroh Hospital for her devoted
time on treating HIV-infected children and adolescents.